1. Field of the Invention
The present invention relates generally to the field of radioimmunotherapy. More specifically, the present invention relates to a Bismuth-213 generator and clinical uses thereof.
2. Description of the Related Art
The therapeutic potential of the alpha-particle emitting radionuclide, 213Bi, in the treatment of single cell neoplastic disorders such as leukemias (Nikula et al., 1998 and Jurcic et al., 1997), lymphomas, and micrometastatic neoplasms (McDevitt et al., 1996) and possibly other cancers and diseases, gives the construction of a stable and reliable radionuclide generator a high priority. Bismuth-213 (213Bi) is a daughter radionuclide of 225Ac and the decay cascade is shown in FIG. 1 (Chang, 1996). There are six predominant radionuclidic daughters of 225Ac which are produced in the cascade to stable 209Bi and for each 225Ac decay there are a number of alpha-particle and beta-particle disintegrations, all of rather high energy. The cumulative 225Ac dose to a small mass of a functionalized organic resin due to 25 mCi 225Ac is substantial and will rapidly cause complete generator failure to occur. Furthermore, the continuous generation of radical species on the resin and in the generator eluate can lead to poor radiochemical labeling yields and poor recovery of labeled antibody product.
Currently published generator technology (Kaspersen et al., 1995 and Geerlings et al., 1993) is not adequate to prepare material for human use. In its published form, virtually no useable Bi-213 can be extracted from the generator when it is loaded with quantities of Ac-225 necessary to achieve human dose levels. This is because the concentrated Ac-225 damages the column material, causes breakdown and fusion of the column media, rapid leakage of Ac-225 from the column as well as leakage of other non-isotopic by-products, and ultimately prevents elution of the column or subsequent labeling reactions. Hence, a dose of Bi-213 suitable for human use could not be obtained from the generator described by Kaspersen or Geerlings (Kaspersen et al., 1995 and Geerlings et al., 1993) despite repeated attempts and the aforementioned problems were not anticipated based on their published methods.
The prior art is deficient in the lack of effective means of producing doses of Bi-213 suitable for clinical labeling for human use. The present invention fulfills this long-standing need and desire in the art.
The present invention is directed to a method for constructing and operating a 225Ac/213Bi generator capable of producing 25-100 mCi of 213Bi suitable for clinical antibody labeling. The generator has been designed to have an effective lifetime of several weeks, producing up to six therapeutic doses of radionuclide per day. To date, 80 clinical doses have been prepared and injected into patients using the described 213Bi generator.
The present invention is also directed to methods of preparing 213Bi-labeled phamarceutical compounds using the 225Ac/213Bi generator and related applications of these labeled compounds.
In one embodiment of the present invention, there is provided a Bi-213 generator comprising a first container containing 225Ac solution; a second container; a column; a third container; and a valve, wherein the valve connects the first container, second container and the column. Preferably, the Bi-213 generator is capable of producing from about 10 mCi to about 100 mCi of Bismuth-213 radioinuclide.
In another embodiment of the present invention, there is provided a method for preparing a Bismuth-213-labeled compound, comprising the steps of: (a) eluting the generator with an elution buffer to obtain an eluate; (b) adding to the eluate with the compound to be labeled for reacting; (c) adding a quench solution to the reaction; and (d) purifying the solution from (c) to obtain a final product, which contains Bismuth-213-labeled compound. Preferably, the processing time for completing all the steps is from about 10 minutes to about 25 minutes. Representative bismuth-213-labeled compound include an antibody, a fragment of an antibody, a cytokine and a receptor ligand.
In still another embodiment of the present invention, there is provided a system for preparing a Bismuth-213-labeled compound, comprising a first container; the Bi-213 generator; a reaction vial; a second container; a column (or a filter); and a third container to collect final product, which contains Bismuth-213-labeled compound.
In still yet another embodiment of the present invention, there is provided a kit for preparing a Bismuth-213-labeled compound based on the above disclosed system.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.